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1 Exposure Data

1.1 Identification of the agent

From (IARC, 2006).

Chem. Abstr. Serv. Reg. No.: 50-00-0

Chem. Abstr. Name: Formaldehyde

IUPAC Systematic Name: Methanal

Synonyms: Formaldehyde gas; formic 

aldehyde; methaldehyde; methyl aldehyde; methylene oxide; oxomethane; 

oxymethylene

C O

H

H

CH2O

Relative molecular mass: 30.03

Description: Colourless gas with a pungent 

odour

Conversion factor: mg/m3

 = 1.23 × ppm; 

calculated from: mg/m3

 = (relative 

molecular mass/24.45) × ppm, assuming 

standard temperature (25 °C) and pressure 

(103.5 kPa).

1.2 Use

Formaldehyde is produced worldwide on a 

large scale by catalytic, vapour-phase oxidation 

of methanol. Formaldehyde is used mainly in the 

production of various types of resin. Phenolic, 

urea, and melamine resins have wide uses as 

adhesives and binders in the wood-production, 

pulp-and-paper, and the synthetic vitreousfibre industries, in the production of plastics 

and coatings, and in textile finishing. Polyacetal 

resins are widely used in the production of plastics. Formaldehyde is also used extensively as an 

intermediate in the manufacture of industrial 

chemicals, such as 1,4-butanediol, 4,4′-methylenediphenyl diisocyanate, penta-erythritol, and 

hexamethylenetetramine. Formaldehyde is used 

directly in aqueous solution (known as formalin) 

as a disinfectant and preservative in many applications (IARC, 2006).

FORMALDEHYDE

Formaldehyde was considered by previous IARC Working Groups in 1981, 1987, 1994, and 

2004 (IARC, 1982, 1987, 1995, 2006). Since that time new data have become available, which 

have been incorporated in this Monograph, and taken into consideration in the present 

evaluation.
IARC MONOGRAPHS – 100F

1.3 Occurrence and exposure

1.3.1 Environmental occurrence and 

exposure

Formaldehyde is found as a natural product 

in most living systems and in the environment. 

It occurs naturally in fruits and some foods, 

and it is formed endogenously in mammals, 

including humans, as a consequence of oxidative metabolism. In addition to these natural 

sources, common non-occupational sources 

of exposure to formaldehyde include combustion processes, e.g. through emissions from 

motor vehicles, power plants, incinerators, 

refineries, wood stoves, and kerosene heaters. 

Formaldehyde may be released from particle 

boards and similar building materials, carpets, 

paints and varnishes, during cooking of some 

foods, and during its use as a disinfectant. It is 

also present in tobacco smoke. An indirect source 

of exposure to formaldehyde is its formation via 

photochemical oxidation of hydrocarbons, such 

as methane, and other precursors emitted from 

combustion processes (NTP, 2005; IARC, 2006). 

Formaldehyde has a short half-life in the environment, because it is removed from the air by 

photochemical processes and by precipitation 

and biodegradation (NTP, 2005).

Concentrations of formaldehyde in outdoor 

air are generally below 0.001 mg/m3

 in remote 

areas and below 0.02 mg/m3

 in urban settings. 

The levels of formaldehyde in indoor air of 

houses are typically 0.02–0.06 mg/m3

; indoor 

combustion sources can significantly increase 

these levels. Cigarettes may contribute as much 

as 10–25% of the indoor exposure. Average 

concentrations of 0.5 mg/m3

 or more have been 

measured in ‘mobile homes’, but these have 

declined since the late 1980s as a result of standards that require that building materials – e.g. 

particle boards – emit lower concentrations of 

formaldehyde. A recent study of emissions from 

mosquito coils found the average concentration of 

formaldehyde exceeded 100 μg/m3 (IARC, 2006, 

2010; Lee & Wang, 2006). Data on formaldehyde 

concentrations in outdoor air in residential and 

public settings, and information on exposure to 

formaldehyde associated with household use of 

solid fuels and high-temperature frying, have 

been reviewed in IARC Monograph Volumes 88 

and 95 (IARC, 2006, 2010).

Automobile exhaust is a major source of 

formaldehyde in ambient air. Recent reports 

suggest that formaldehyde emissions may be 

higher from vehicles powered by compressed 

natural gas compared with those running on 

ethanol or gasohol (Corrêa & Arbilla, 2005), and 

that these emissions may be decreased by substitution of an ethanol-biodiesel-diesel blend for 

diesel fuel (Shi et al., 2006). In addition, formaldehyde can be absorbed through the skin from 

cosmetics or via contact with other consumer 

products containing formaldehyde, such as 

unwashed permanent-press fabrics treated with 

formaldehyde-releasing resins (NTP, 2005).

1.3.2 Occupational exposure

Occupational exposure to formaldehyde 

occurs in a wide variety of occupations and 

industries. CAREX (CARcinogen EXposure) 

is an international information system on 

occupational exposure to known and suspected 

carcinogens based on data collected in the 

European Union (EU) from 1990 to 1993. The 

CAREX database provides selected exposure 

data and documented estimates of the number 

of exposed workers by country, carcinogen, 

and industry (Kauppinen et al., 2000). Table 1.1

presents the results for formaldehyde in the EU 

by industry (CAREX, 1999).

In IARC Monograph Volume 88 (IARC, 2006) 

data were reviewed on occupational exposure to 

formaldehyde by type of industry. The highest 

continuous exposures (2–5 ppm; 2.5–6.1 mg/m3

) 

were measured in the past during varnishing of 

furniture and wooden floors, in the finishing of 

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Formaldehyde

403

Table 1.1 Estimated numbers of workers exposed to formaldehyde above background levels in 

the European Union

Industry, occupational activity

Manufacture of furniture and fixtures, except primarily of metal 179000

Medical, dental, and other health and veterinary services 174000

Manufacture of wearing apparel, except footwear 94000

Manufacture of wood and wood and cork products, except furniture 70000

Personal and household services 62000

Construction 60000

Manufacture of textiles 37000

Iron and steel basic industries 29000

Manufacture of fabricated metal products, except machinery 29000

Manufacture of other non-metallic mineral products 23000

Manufacture of machinery, except electrical 20000

Manufacture of industrial chemicals 17000

Manufacture of other chemical products 17000

Manufacture of plastic products not classified elsewhere 16000

Agriculture and hunting 16000

Manufacture of paper and paper products 13000

Printing, publishing and allied industries 13000

Wholesale and retail trade and restaurants and hotels 13000

Manufacture of transport equipment 11000

Manufacture of electrical machinery, apparatus and appliances 10000

Manufacture of footwear 9000

Manufacture of glass and glass products 8000

Research and scientific institutes 7000

Non-ferrous metal basic industries 6000

Manufacture of leather and products of leather or of its substitutes 6000

Beverage industries 4000

Manufacture of instruments, photographic and optical 4000

Other manufacturing industries 3000

Food manufacturing 3000

Crude petroleum and natural gas production 2000

Manufacture of rubber products 4000

Financing, insurance, real estate and business services 3000

Education services 2000

Sanitary and similar services 2000

Services allied to transport 2000

Manufacture of miscellaneous products of petroleum and coal 1000

Other industries 2000

Total (all industries) 971000

From Kauppinen et al. (2000), CAREX (1999)
IARC MONOGRAPHS – 100F

textiles, in the garment industry, in the treatment 

of fur, and in certain jobs within manufactured 

board mills and foundries. Short-term exposures 

to high levels (3 ppm and higher; ≥ 3.7 mg/m3

) 

have been reported for embalmers, pathologists, 

and paper workers. Lower concentrations have 

usually been encountered during the manufacture of man-made vitreous fibres, abrasives and 

rubber, and in formaldehyde-production industries. A very wide range of exposure levels has 

been observed in the production of resins and 

plastic products. The development of resins that 

release less formaldehyde, and improved ventilation have resulted in lower exposure levels 

in many industrial settings in recent decades 

(IARC, 2006).

2. Cancer in Humans

2.1 Cancer of the nasopharynx

In IARC Monograph Volume 88 (IARC, 2006) 

it was concluded that there was sufficient evidence

for the carcinogenicity of formaldehyde, based 

primarily on its association with nasopharyngeal cancer. There have been relatively few new 

studies published on this association since that 

time, although there have been several re-evaluations and meta-analyses.

2.1.1 Cohort studies

In the most recent follow-up of the largest 

cohort study from the USA of industrial workers 

exposed to formaldehyde, a statistically significant excess of deaths from nasopharyngeal 

cancer was observed in comparison with the US 

national population, with statistically significant 

exposure–response relationships for peak exposure and cumulative exposure (Hauptmann et al.,

2004; see Table 2.1 available at http://monographs.

iarc.fr/ENG/Monographs/vol100F/100F-24-

Table2.1.pdf). Based on eight cases, a significant 

excess mortality from nasopharyngeal cancer 

was observed among formaldehyde-exposed 

workers (SMR, 2.10; 95%CI: 1.05–4.21). A highly 

statistically significant (Ptrend < 0.001) exposure–

response relationship was observed between 

peak-exposure to formaldehyde and risk for 

nasopharyngeal cancer in a Poisson regressionanalysis. All exposed cases were in the highest 

category of peak-exposure, and the relative risk 

was 1.83. This analysis excluded one case which, 

according to cancer registry data, had been 

misclassified as nasopharyngeal cancer. Weaker 

exposure–response relationships were observed 

between nasopharyngeal cancer and average or 

cumulative exposure, and duration of exposure 

(Ptrend = 0.07, 0.03 and 0.15, respectively).

In the two other large cohort studies of industrial workers, cases of nasopharyngeal cancer 

were fewer than expected, but the power of these 

studies to detect an effect on nasopharyngeal 

cancer was low and the deficits were small. In the 

first study, of British chemical workers, one death 

was observed when 2.0 were expected (Coggon 

et al., 2003); in the second study, no deaths were 

observed among US garment-manufacturers, 

where 0.96 were expected (Pinkerton et al., 2004).

An excess of deaths from nasopharyngeal 

cancer was observed in a proportionate mortality 

analysis of the largest US cohort of embalmers 

(Hayes et al., 1990) and in a Danish study of 

proportionate cancer incidence among workers 

at companies that used or manufactured formaldehyde (Hansen & Olsen, 1995; see Table  2.2 

available at http://monographs.iarc.fr/ENG/

Monographs/vol100F/100F-24-Table2.2.pdf).

Marsh et al. (1996) conducted a cohort study 

in one of the plants considered in the NCI study 

(where five of the nine cases of nasopharyngeal 

cancer occurred). The cohort included earlier 

year of entry and was enumerated independently. 

Significantly increased mortality due to nasopharyngeal cancer was observed among formaldehyde-exposed workers compared with US and 

regional populations (Connecticut State and 

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Formaldehyde

local county). In a recent follow-up through 2003, 

Marsh et al. (2007a) showed elevated SMRs when 

both national and local county rates were used. In 

addition, when conducting a case–control study 

nested within the cohort and including seven 

deaths from nasopharyngeal cancer, the authors 

obtained information on employment outside 

the formaldehyde industry and showed that five 

of these workers had been employed as a silversmith. However, while there was some evidence 

of effect modification by activities as a silversmith (based on small numbers), confounding 

alone did not explain the relatively high number 

of deaths from nasopharyngeal cancer in this 

plant (Marsh et al., 2007a).

Two analyses have been conducted to 

re-analyse the data from the most recent update 

of the NCI cohort, with a focus on solid tumours 

(Hauptmann et al., 2004). The first included 

an analysis of exposure category and SMR, as 

well as an analysis of Plant 1, where five of nine 

deaths from nasopharyngeal cancer occurred, 

compared with all other plants in the cohort 

(Marsh & Youk, 2005). Using their own cutpoints of exposure, the authors concluded that 

their analysis lent uncertainty to the findings 

from the NCI cohort. In another re-analysis, the 

authors further controlled for the effect of plant 

for the peak-exposure metric and performed 

sensitivity analyses by imputing additional cases, 

which showed instability in the risk estimates 

(Marsh et al., 2007b). The authors concluded that 

an interaction between plant group and exposure 

makes generalization beyond Plant 1 difficult.

2.1.2 Case–control studies

The relationship between nasopharyngeal 

cancer and exposure to formaldehyde has also 

been investigated in seven case–control studies, 

five of which found elevated risks for overall 

exposure to formaldehyde or in higher exposure categories, although not all were statistically significant (see Table  2.3 available at 

http://monographs.iarc.fr/ENG/Monographs/

vol100F/100F-24-Table2.3.pdf; Vaughan 

et al., 1986b; Roush et al., 1987; West et al., 1993; 

Vaughan et al., 2000; Hildesheim et al., 2001). 

One study found an elevation among women, 

but not men (Olsen et al., 1984) and one found 

no evidence of an association (Armstrong et al.,

2000). Two case–control studies were considered as the most informative because of their 

size, their exposure assessment, and the evaluation of potential confounders. The first, a population-based case–control study in the USA, 

showed a significant association for the workers 

whose exposure duration had been the longest 

(OR = 2.1; 95%CI: 1.0–4.5, Ptrend = 0.07), but not 

for maximum exposure (Ptrend = 0.57) (Vaughan 

et al., 2000). When the analysis was limited to 

differentiated squamous-cell and epithelial NOS, 

there was a significant association in the highest 

exposure category for both duration and cumulative exposure with significant exposure-response 

trends (Ptrend = 0.014 and 0.033, respectively). In 

the other study, conducted in Taiwan, China, 

an OR of 1.6 (95%CI: 0.91–2.9, Ptrend = 0.08) was 

found in the category with the longest duration of exposure (Hildesheim et al., 2001). For 

cumulative exposure, there was a non-significant 

elevation in the highest exposure category and 

the trend test was not significant (P = 0.10). In 

subanalyses that were restricted to cases and 

controls who were seropositive for antibodies 

against Epstein-Barr virus, the association 

between exposure to formaldehyde and nasopharyngeal cancer appeared to be stronger, with 

an OR for ever exposure of 2.7 (95%CI: 1.2–6.2). 

However, no clear dose–response pattern was 

observed with increasing duration of exposure, 

or with estimated cumulative exposure.

2.1.3 Meta-analyses

A meta-analysis published in 1997 included 

some but not all of the above studies, and found 

an overall meta-relative risk for nasopharyngeal 

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IARC MONOGRAPHS – 100F

cancer of 1.3 (95%CI: 1.2–1.5) (Collins et al.,

1997). From a pooled analysis including the three 

recently updated industrial cohorts (Coggon 

et al., 2003; Hauptmann et al., 2004; Pinkerton 

et al., 2004), Bosetti et al. (2008) reported an 

overall SMR of 1.33 (95%CI: 0.61–2.53). A 

recently published meta-analysis included both 

case–control studies (n = 6) and cohort studies 

(n = 7) (Bachand et al., 2010). For the case–control 

studies, the overall OR was 1.22 (95%CI: 1.00–

1.50), with the meta-regression OR no longer 

significant when limited to studies that included 

adjustment for socioeconomic status, smoking or 

location. The risk estimate for cohort studies was 

0.72 (95%CI: 0.40–1.29), including seven studies 

(Bachand et al., 2010). For the cohort studies, 

the authors used a re-analysis of the NCI cohort 

study from which Plant 1 was left out (Marsh & 

Youk, 2005).

2.2 Leukaemia

In IARC Monograph Volume 88 (IARC, 

2006) it was concluded that there was strong, 

but not sufficient evidence for the leukaemogenic effects of formaldehyde. Since that time, 

an update to the NCI cohort and a nested 

case–control study of workers in the funeral 

industry have been published (Beane Freeman 

et al., 2009; Hauptmann et al., 2009), as well 

as three meta-analyses (Bosetti et al., 2008; 

Zhang et al., 2009; Bachand et al., 2010; see 

Table  2.1 online, and Table  2.5 available at 

http://monographs.iarc.fr/ENG/Monographs/

vol100F/100F-24-Table2.5.pdf).

2.2.1 Cohort studies

Excess mortality from leukaemia has been 

observed relatively consistently in studies of 

professional workers (i.e. embalmers, funeral 

parlour workers, pathologists and anatomists), 

with six mortality studies showing positive associations (Walrath & Fraumeni, 1983, 1984; Levine 

et al., 1984; Stroup et al., 1986; Hayes et al., 1990; 

Hall et al., 1991) and one not (Logue et al., 1986; 

see Table 2.2 online).

A weakness of the proportionate mortality 

studies among professionals has been the lack 

of exposure assessment. A recently published 

nested case–control study conducted among 

professionals in the funeral industry examined 

lifetime work practices and exposure in the 

funeral industry to develop metrics of exposure among this group, which included duration of jobs held while embalming, number of 

embalmings, average intensity of embalming and 

peak exposure (Hauptmann et al., 2009). Details 

of work practices were obtained by interviews 

with next of kin and co-workers. Positive associations were seen – at many levels of exposure and 

for multiple exposure metrics – for deaths from 

lymphohaematopoietic malignancies of nonlymphoid origin (n = 48). For myeloid leukaemia 

(n  =  34) the OR was 13.6 (95%CI: 1.6–119.7; 

Ptrend = 0.020) for the longest duration of work in 

jobs with embalming. Because only one case was 

reported to have never embalmed, additional 

analyses were conducted in which those who 

reported to have embalmed ≤  500 times were 

taken as the referent group, to provide a more 

stable estimate. Results were attenuated, but still 

significant (OR  =  3.9; 95%CI: 1.2–12.5). [There 

was a considerable amount of missing data that 

required imputation for analyses.]

The findings for leukaemia in studies of professional workers appeared to be contradicted by the 

lack of such findings among industrial workers. 

However, some evidence for an excess of deaths 

from leukaemia has been reported in the recent 

updates of two of the three major cohort studies 

of industrial workers. Since the previous evaluation (IARC, 2006), the NCI cohort of industrial 

workers in the USA has been updated with an 

additional ten years of mortality data resulting 

in 123 deaths from leukaemia, including 48 from 

myeloid leukaemia (Beane Freeman et al., 2009). 

This update extended the mortality follow-up 

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Formaldehyde

through 2004 and included additional deaths 

before 1994 that had not been previously considered. Risk estimates from follow-up through 

2004 were diminished for leukaemia and 

myeloid leukaemia compared with the follow-up 

through 1994 (Hauptmann et al., 2003), when 

both conditions had been significantly associated with increasing peak-exposure and average 

intensity of exposure to formaldehyde. As in 

the previous analysis of leukaemia, the association in the most recent update was stronger for 

myeloid leukaemia and peak exposure than for 

lymphatic leukaemia and for other metrics of 

exposure (Beane Freeman et al., 2009). However, 

because the last known exposure occurred in 

1980 and median follow-up was over 40 years, 

the authors not only examined risks at the end 

of follow-up in 2004, but also assessed associations over time by extending follow-up in yearly 

increments. Risks appeared to be highest before 

1980, but only achieved statistical significance 

in the mid-1990s, when a sufficient number of 

deaths had accrued. Additional analyses with 

time since first exposure and time since first high 

peak-exposure indicated that risks were highest 

during the first twenty-five years. Patterns were 

similar, but attenuated, for average intensity of 

exposure; no association was observed with 

cumulative exposure.

Mortality from leukaemia was also found 

to be in excess in an update of the study of US 

garment workers exposed to formaldehyde 

(Pinkerton et al., 2004). A small and statistically non-significant excess was observed for the 

entire cohort in comparison with rates among 

the general population (SMR  =  1.09; 95%CI: 

0.7–1.63). This excess was somewhat stronger for 

myeloid leukaemia (SMR  =  1.44; 95%CI: 0.80–

2.37), which is consistent with the findings from 

the study of industrial workers in the USA and 

several of the studies of medical professionals 

and embalmers. The excess was also stronger 

among workers with a longer duration of exposure and longer follow-up, and among those who 

had been employed early in the study period 

when exposures to formaldehyde were believed 

to be highest. The positive associations observed 

in the subgroup analyses presented in the study 

of US garment workers were based on a relatively 

small number of deaths, and were thus not statistically stable.

The updated study of British industrial 

workers found no excess mortality for leukaemia 

among all workers exposed to formaldehyde 

(SMR = 0.91; 95%CI: 0.62–1.29) or among those 

with the highest exposure (SMR = 0.71; 95%CI: 

0.31–1.39) (Coggon et al., 2003). The lack of positive findings in this study is difficult to reconcile 

with the findings from the studies of garment 

workers and industrial workers in the USA, 

and with the results of studies on professionals 

exposed to formaldehyde. This British study is 

a relatively large, high-quality study with sufficiently long follow-up to have had a reasonable chance to detect an excess of deaths from 

leukaemia. It did not examine specifically the 

risk for myeloid leukaemia, which represented 

the strongest finding in the studies of garment 

workers and industrial workers in the USA and 

in several of the studies of medical professionals 

and funeral workers.

2.2.2 Case–control studies

Three case–control studies evaluated exposure to formaldehyde and risk for leukaemia 

(Linos et al., 1990; Partanen et al., 1993; Blair et al.,

2001; Table 2.5 online). However, the numbers of 

exposed cases were few, and no significant elevations of risk were found.

2.2.3 Meta-analyses

A meta-analysis published in 2004 for ‘ever 

exposure’ to formaldehyde and leukaemia 

included eighteen studies and presented separate analyses by type of job: for industrial 

workers, the mRR was 0.9 (95%CI: 0.8–1.0); for 

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IARC MONOGRAPHS – 100F

embalmers 1.6 (95%CI: 1.2–2.0); and for pathologists and anatomists 1.4 (95%CI: 1.0–1.9), with an 

overall mRR of 1.1 (95%CI: 1.0–1.2) (Collins & 

Lineker, 2004). In another meta-analysis, analysis was restricted to 13 cohort or proportionate 

mortality studies and similar results were found, 

with a pooled RR based on the weighted average 

of the SMRs for leukaemia among industrial 

workers of 0.9 (95%CI: 0.75–1.07), based on 122 

deaths, and of 1.39 (95%CI: 1.15–1.68) among 

professionals, based on 106 deaths (Bosetti et al.,

2008). A further meta-analysis differed from 

these two previous ones by excluding all proportionate mortality studies and including the most 

recent update of the NCI cohort (Bachand et al.,

2010). For leukaemia overall, a risk estimate of 

1.05 (95%CI: 0.93–1.20) was calculated for ‘ever 

exposure’, based on 15 studies with the use of 

a fixed-effects model. For myeloid leukaemia, 

the calculated mRR was  1.09 (95%CI: 0.84–

1.40, based on three studies) and for lymphatic 

leukaemia the mRR was 1.11 (95%CI: 0.81–1.52, 

based on two studies).

Zhang et al. (2009) published a meta-analysis that included 15 cohort or case–control 

studies. The authors selected only studies where 

it was clear that the workers had been exposed 

to formaldehyde. In contrast to the other metaanalyses, this one used one exposure metric from 

each study and considered the highest exposure 

category for calculating the mRR. For leukaemia, 

the mRR was 1.54 (95%CI: 1.18–2.00). In addition, a separate analysis of myeloid leukaemia 

– for the six studies that reported it – found an 

mRR of 1.90 (95%CI: 1.31–2.76).

2.3 Cancer of the nasal sinuses

2.3.1 Cohort studies

An analysis of proportionate cancer incidence among industrial workers in Denmark 

showed an increased risk for squamous-cell 

carcinomas (Hansen & Olsen, 1995, 1996). No 

excess of mortality from sinonasal cancer was 

observed in the three recently updated studies of 

industrial and garment workers in the USA, and 

of chemical workers in the United Kingdom (see 

Table 2.1 online; Coggon et al., 2003; Hauptmann 

et al., 2004; Pinkerton et al., 2004).

2.3.2 Case–control studies

The association between exposure to formaldehyde and the risk for sinonasal cancer has been 

evaluated in six case–control studies that primarily focused on formaldehyde (see Table  2.4 

available at http://monographs.iarc.fr/ENG/

Monographs/vol100F/100F-24-Table2.4.pdf; 

Olsen et al., 1984; Hayes et al., 1986; Olsen & 

Asnaes, 1986; Vaughan et al., 1986a; Roush et al.,

1987; Luce et al., 1993; Pesch et al., 2008). Four 

of these six studies reported an increased risk 

(Olsen et al., 1984; Hayes et al., 1986; Vaughan 

et al., 1986a; Luce et al., 1993).

2.3.3 Pooled analysis

Four of the cohort studies contributed to a 

pooled analysis that collated occupational data 

from 12 case–control investigations (Luce et al.,

2002). After adjustment for known occupational 

confounders, this analysis showed an increased 

risk for adenocarcinoma associated with high 

exposure (> 1 ppm) to formaldehyde in both men 

(OR, 3.0; 95%CI: 1.5–5.7) and women (OR, 6.3; 

95%CI: 2.0–19.7). An exposure–response trend 

was observed in relation to an index of cumulative exposure. There was some evidence of an 

association with squamous-cell carcinoma.

[Most epidemiological studies of sinonasal 

cancer have not distinguished between tumours 

that arise in the nose and those that develop in 

the nasal sinuses. Thus, any effect on the risk 

for nasal cancer specifically would tend to be 

diluted if there were no corresponding effect on 

the risk for cancer in the sinuses and could mask 

its detection, particularly in cohort studies that 

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Formaldehyde

have relatively low statistical power. However, 

the apparent discrepancy between the results of 

the case–control as compared with the cohort 

studies might also reflect residual confounding 

by wood dust in the former. Almost all of the 

formaldehyde-exposed cases in the case–control 

studies were also exposed to wood dust, which 

resulted in a high relative risk, particularly for 

adenocarcinomas.]

2.4 Other cancers

Several studies have identified statistically significant positive associations between 

exposure to formaldehyde and cancer at other 

sites, including the oral cavity, oro-and hypopharynx, larynx, lung, brain, pancreas, Hodgkin 

lymphoma, and multiple myeloma. However, the 

results are inconsistent (see Tables  2.4 and  2.5 

online; Table  2.6 available at http://monographs.iarc.fr/ENG/Monographs/vol100F/100F24-Table2.6.pdf, and Table  2.7 available at 

http://monographs.iarc.fr/ENG/Monographs/

vol100F/100F-24-Table2.7.pdf).

2.5 Synthesis

The Working Group noted one industrial 

cohort study with both a strong overall association between exposure to formaldehyde and 

nasopharyngeal cancer, and the most elevated 

risks in the highest exposure category. Positive 

associations were also observed in many of the 

case–control studies, in particular those of larger 

size and higher-quality exposure assessment. 

While there was no association observed in the 

two other large industrial cohort studies, the 

expected number of cases in those studies was 

quite small. It is concluded that occupational 

exposure to formaldehyde causes nasopharyngeal cancer in humans. The Working Group 

noted that it was unlikely that confounding or 

bias could explain the observed association.

Elevated risks of leukaemia have been 

consistently observed in proportionate mortality 

studies of professionals exposed to formaldehyde (i.e. embalmers, workers in the funeral 

industry, pathologists and anatomists). Results 

from a nested case–control study of workers 

in the funeral industry show elevated risks for 

many measures of exposure, which are strongest 

for myeloid leukaemia. In two of the three large 

industrial cohort studies positive associations 

were observed for leukaemia, which were somewhat stronger for myeloid leukaemia. It is difficult to reconcile the lack of association observed 

in the third industrial cohort study with the 

overall positive associations in the others. 

However, there seems to be no strong evidence 

that confounding or bias explains the positive associations seen in multiple settings. On 

balance, the Working Group concluded that the 

epidemiologic evidence shows that occupational 

exposure to formaldehyde causes leukaemia.

Many case–control studies show positive 

associations for exposure to formaldehyde and 

sinonasal cancer, some with evidence of an 

exposure–response pattern. However, many 

of these cases were also exposed to wood dust, 

which was strongly associated with sinonasal 

cancer in these studies. The industrial cohort 

studies show no such association, which may be 

due to lack of statistical power, or could indicate 

that uncontrolled confounding to wood dust 

partially explains the observed associations in 

the case–control studies. The Working Group 

could not rule out the possibility of residual 

confounding in the case–control studies and 

noted the discordant results between the cohort 

and case–control studies.

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IARC MONOGRAPHS – 100F

3. Cancer in Experimental Animals

Carcinogenicity studies with mice, rats and 

hamsters exposed to formaldehyde by inhalation, 

via the drinking-water, or through the skin were 

reviewed in IARC Monograph Volume 88 (IARC, 

2006). Results of adequately conducted carcinogenicity studies are summarized in Table  3.1. 

There have been no additional carcinogenicity 

studies in experimental animals reported since 

the previous review.

3.1 Inhalation

In one inhalation study in B6C3F1 mice, 

formaldehyde marginally increased the incidence of squamous cell carcinomas of the nasal 

cavity in males. The incidence of lymphoma in 

females exposed to 14.3 ppm (27/121) was also 

marginally increased (P = 0.06) when compared 

(pair-wise) with controls (19/121) (CIIT, 1981; 

Kerns et al., 1983a, b; Gibson, 1984).

In six studies (Swenberg et al., 1980; CIIT, 

1981; Albert et al., 1982; Kerns et al., 1983a, b; 

Gibson, 1984; Sellakumar et al., 1985; Feron, 

et al., 1988; Woutersen et al., 1989; Monticello 

et al., 1996; Kamata et al., 1997) in different 

strains of rats (F344, Wistar, and SpragueDawley), there were treatment-related increases 

in tumours of the nasal cavity (primarily squamous-cell carcinomas but also squamous-cell 

papillomas, polypoid adenomas, carcinomas, 

rhabdomyosarcomas, adenocarcinomas, and 

mixed/combined tumours). In one study 

(CIIT, 1981), the incidences of undifferentiated 

leukaemia [Fischer rat leukaemia, as indicated 

in the report] were 12/120 (control), 17/120 (2 

ppm), 16/120 (5.6 ppm) and 7/120 (14.3 ppm) in 

females; there was a marked decrease in survival 

in the animals exposed to the high dose. Based 

on a survival-adjusted analysis, the incidence of 

leukaemia in females exposed to 14.3 ppm was 

increased compared with controls (P  =  0.0056; 

Tarone-extension of the Cox test; level of significance, P < 0.0167). [The Working Group noted 

that this type of leukaemia is a very common, 

spontaneously occurring neoplasm in the F344 

rat strain].

3.2 Oral administration (drinkingwater)

In one drinking-water study in male Wistar 

rats, there was a treatment-related increase 

in fore-stomach squamous-cell papillomas 

(Takahashi et al., 1986). Another study in male 

and female Wistar rats did not report any increase 

in tumours (Til et al., 1989).

In a study with life-long exposure to formaldehyde, beginning in utero (transplacentally), there 

was an increased incidence of smooth-muscle 

tumours of the small intestine (leiomyosarcoma) 

in female offspring (Soffritti et al., 1989). In 

another study in male and female rats, increased 

incidences of total malignant tumours, haematopoietic tumours, and interstitial-cell adenomas 

were observed in males (Soffritti et al., 1989, 2002). 

[The Working Group reaffirmed the concerns 

of the previous Working Group (IARC, 2006) 

regarding the pooling of all ‘leukaemias’ diagnosed as lymphoblastic leukaemias and lymphosarcomas, immunoblastic lymphosarcomas, and 

“other types” of leukaemia and haemolymphoreticular sarcomas. Also noted were the lack of 

reporting of non-neoplastic lesions and historical 

control data, and the numerous discrepancies 

in tumour incidence between the first (Soffritti 

et al., 1989) and second report (Soffritti et al.,

2002) of the results of this study].

3.3 Skin application

In one study in male and female hairless Oslo 

mice, topical application of 10% formaldehyde in 

water reduced the latency of 7,12-dimethylbenz[a]

anthracene-induced skin tumours (Iversen, 

1986).

410
Formaldehyde

411

Table 3.1 Carcinogenicity studies in experimental animals exposed to formaldehydeSpecies, strain (sex)DurationReference

Dosing regimen,Animals/group at start

Incidence of tumours Significance Comments

Inhalation studies

C3H mouse (unspecified)35 wk (some for 64 wk)Horton et al. (1963)

0, 50, 100, 200 mg/m3

1 h/d, 3 d/wk42–60/group

No pulmonary tumours NS USP grade

Due to severe toxicity, exposure to 200 mg/m3 was discontinued after the 11th

exposure. Thirty-six mice exposed to 50 mg/m3 were exposed to 150 mg/m3 for 

29 additional wk. Basal-cell hyperplasia, squamous metaplasia and atypical hyperplasia were observed in trachea and bronchi of many exposed mice. Nasal tissues were not examined.Short period of exposure and short duration of study.

B6C3F1 mouse (M)30 moKerns et al. (1983a, b), 

Gibson (1984)

0, 2, 5.6, 14.3 ppm (0, 2.5, 6.9, 17.6 mg/m3)

6 h/d, 5 d/wk for 24 mo119–120/group

No increased tumour incidence > 97.5% purity

Interim sacrifices (10/group) at 6 and 12 mo; 0–1 at 18 mo; 17–21 at 24 mo. Squamous-cell hyperplasia, metaplasia and dysplasia were commonly present in nasal passages of mice exposed to 14.3 ppm.

Nasal cavity (malignant)a: 2/17 (14.3 

ppm) vs 0/21 (controls) at 24 mo

NS

B6C3F1 mouse (F)30 moKerns et al. (1983a, b), 

Gibson (1984), CIIT (1981)

0, 2, 5.6, 14.3 ppm (0, 2.5, 6.9, 17.6 mg/m3)

6 h/d, 5 d/wk for 24 mo120–121/group

No increased tumour incidence > 97.5% purity

Interim sacrifices (10/group) at 6 and 12 mo; 19–20 at 18 mo; 26–41 at 24 mo; 9–16 at 27 mo. Squamous-cell hyperplasia, metaplasia and dysplasia were commonly present in nasal passages of mice exposed to 14.3 ppm.

Lymphoma: 27/121 (14.3 ppm) vs 19/121 (controls)

NS (P = 0.06)
IARC MONOGRAPHS – 100F

412

Species, strain (sex)DurationReference

Dosing regimen,Animals/group at start

Incidence of tumours Significance Comments

F344 rat (M)30 moSwenberg et al. (1980), 

Kerns et al. (1983a, b), 

Gibson (1984)

0, 2, 5.6, 14.3 ppm (0, 2.5, 6.9, 17.6 mg/m3

)

6 h/d, 5 d/wk for 24 mo119–120/group

Nasal cavity (malignant)a: 0/118, 0/118, 

1/119, 51/117*

*P < 0.001 > 97.5% purity

Interim sacrifices (10/group) at 6 and 12 mo; 20 at 18 mo; 13–54 at 24 mo; 5–10 at 27 mo; 0–6 at 30 mo. Squamous-cell hyperplasia, metaplasia and dysplasia were commonly present in nasal passages of rats exposed to 14.3 ppm.

Nasal cavity (malignant)b: 0/118, 0/118, 

0/119, 4/117

NS

Nasal cavity (benign)c: 1/118, 4/118, 

6/119, 4/117

NS

F344 rat (F)30 moSwenberg et al. (1980), 

Kerns et al. (1983a, b), 

Gibson (1984), CIIT (1981)

0, 2, 5.6, 14.3 ppm (0, 2.5, 6.9, 17.6 mg/m3

)

6 h/d, 5 d/wk for 24 mo120/group

Nasal cavity (malignant)a: 0/114, 0/118, 

1/116, 52/115*

*P < 0.001 > 97.5% purity

Interim sacrifices (10/group) at 6 and 12 mo; 19–20 at 18 mo; 14–47 at 24 mo; 0–10 at 27 mo; 0–5 at 30 mo. Squamous-cell hyperplasia, metaplasia and dysplasia were commonly present in nasal passages of rats exposed to 14.3 ppm.

Nasal cavity (malignant)b: 0/114, 0/118, 

0/116, 1/115

NS

Nasal cavity (benign)c: 0/114, 4/118, 

0/116, 1/115

NS

Haematopoietic tissue (spleen, F344 rat leukaemia diagnosed as undifferentiated leukaemia): 12/120, 17/120, 16/120, 7/120

P = 0.0056; Tarone-extension of the Cox test (adjustment for mortality), level of significance is P < 0.0167

Sprague-Dawley rat (M)LifetimeAlbert et al. (1982); Sellakumar et al. (1985)

0, 14.3 ppm (0, 17.6 mg/m3

)

6 h/d, 5 d/wk99–100/group

Nasal cavity (malignant)a: 0/99, 38/100

P ≤ 0.001 A mixed carcinoma and fibrosarcoma of 

the nasal cavity was also present in the formaldehyde-treated group. Nasal cavity (benign): 0/99, 10/100

P ≤ 0.001

Table 3.1 (continued)
Formaldehyde

413

Species, strain (sex)DurationReference

Dosing regimen,Animals/group at start

Incidence of tumours Significance Comments

Wistar rat (M)126 wkFeron et al. (1988)

0, 10, 20 ppm (0, 12.3 or 25 mg/m3)

6 h/d, 5 d/wk for 4, 8 or 13 wk45/group/interval

Nasal cavity: 2/134, 2/132, 10/132 (denominator combines all intervals of exposure for control and treated groups); the authors considered 6/10 tumoursd in the high-dose group as 

treatment-related.

NR Purity NR

Hyperplasia and metaplasia of nasal epithelium were observed in all rats exposed to formaldehyde. Authors considered most nasal-cavity tumours in the high-dose group to be related to the treatment.

Wistar rat (M)28 moWoutersen et al. (1989)

0, 0.1, 1, 10 ppm (0, 0.123, 1.23, and 12.3 mg/m3) 

6 h/d, 5 d/wk for 3 or 28 mo30/group (U: undamaged) or 60/group (D: damaged)

Nasal cavity (malignant)e:

28 mo exposureU: 0/26, 1/26, 1/26, 1/26D: 1/54, 1/58, 0/56, 17/58*3 mo exposureU: 0/26, 0/30, 0/29 2/26D: 0/57, 2/57, 2/53, 2/54

*[P < 0.001; Fisher’s exact test]

Purity NRMucosa severely damaged by electrocoagulation during the first wk.Eight squamous-cell carcinomas from the nasolacrimal duct were excluded by the authors.

Sprague Dawley rat (F)104 wkHolmström et al. (1989)

0, 12.4 ppm (0, 15.3 mg/m3) 

6 h/d, 5 d/wk16/group

Nasal cavity: 0/16, 1/16a NS Purity NR

Pronounced squamous-cell metaplasia and/or dysplasia in 10/16 rats exposed to formaldehyde vs 0/15 controls. Small group-size noted.

F344 rat (M)24 mo Monticello et al. (1996)

0, 0.69, 2.05, 6.01, 9.93, 14.96 ppm (0, 0.84, 2.4, 7.2, 12, 19 mg/m3)

6 h/d, 5 d/wk90 or 147 (high dose group only)/group

Nasal cavity (malignant)a: 0/90, 0/90, 

0/90, 1/90, 20/90, 69/147*

NR,*[P < 0.001] Formaldehyde vapour of paraformaldehyde

Interim sacrifices at 3, 6, 12 and 18 mo (6/group). Nasal cavity (benign)c: 0/90, 0/90, 0/90, 

0/90, 5/90, 14/147$

One nasal rhabdomyosarcoma and nasal adenocarcinoma each present in groups given 9.93 and 14.96 ppm

NR,$[P < 0.02]

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

414

Species, strain (sex)DurationReference

Dosing regimen,Animals/group at start

Incidence of tumours Significance Comments

F344 rat (M)28 moKamata et al. (1997)

0, 0, 0.3, 2.17, 14.85 ppm (0, 0, 0.36, 2.6, 17.8 mg/m3

)

6 h/d, 5 d/wk32/group (one roomair control and one methanol-exposed control group)

Nasal cavity (malignant)a: 0/32, 0/32, 

0/32, 0/32, 13/32*

*P < 0.01 Formaldehyde vapour of 37% aqueous 

formaldehyde solution with 10% methanol (4.2 ppm)Interim sacrifices at 12, 18 and 24 mo (5/group). Nasal cavity (benign)f: 0/32, 0/32, 0/32, 

0/32, 3/32

NR

Rat (strain not specified) (F)LifetimeYanysheva et al. (1998)

0, 0.003, 0.03, 0.3 mg/m3

,

7 h/d, 5 d/wk for 12 moIntratracheal injection of a total dose of 0, 0.02, 0.1 or 5.0 mg B[a]P/animal over 20 wk50/group

Lung tumours:24/35 (68.6%, 5.0 mg B[a]P + 0.3 mg/m3 formaldehyde) vs 8/28 (28.1%, 5.0 

mg B[a]P)

P < 0.01 Purity NR

Promotion effect

Hamster, Syrian golden (M)LifetimeDalbey (1982)

0, 10 ppm (0, 12.3 mg/m3

)

5 h/d, 5 d/wk88/group (132 controls)

No tumours - Purity NR

Hyper- and metaplastic areas were each observed in the nasal epithelium of 5% of exposed animals

Hamster, Syrian golden (M)LifetimeDalbey (1982)

0, 30 ppm (0, 36.9 mg/m3

)

5 h/d, 5 d/wk50/group

No tumours - Purity NR

Hamster, Syrian golden (M)LifetimeDalbey (1982)

0, 30 ppm (0, 36.9 mg/m3

)

5 h/d, 5 d/wkBoth groups subcutaneously injected wkly with 0.5 mg NDEA for 10 wk50/group

Tracheal tumours:[~2.8 tumours/tumour-bearing animal (NDEA + formaldehyde) vs ~1.7 tumours/tumour-bearing animal (NDEA)]

P < 0.05 Purity NR

Promotion effect

Drinking-water studies

Wistar rat (M) 40 wkTakahashi et al. (1986)

Experiment #10 or 0.5% formaldehyde10/group

Fore-stomach squamous-cell papillomas:8/10 vs 0/10

P < 0.01 Purity NR

Table 3.1 (continued)
Formaldehyde

415

Species, strain (sex)DurationReference

Dosing regimen,Animals/group at start

Incidence of tumours Significance Comments

Wistar rat (M)40 wkTakahashi et al. (1986)

Experiment #20 and 0.5% formaldehyde.MNNG administered in the drinking-water to both groups for first 8 wk with a diet containing 10% NaCl30 (control) and 17/group

Adenocarcinoma of the pylorus:4/17 vs 1/30

P < 0.05 Purity NR

Weak promotion of tumour incidence in the glandular stomach. Incidence of forestomach papillomas was also increased vs controls, but was similar to that in the group treated with formaldehyde only (experiment #1)

Wistar rat (M)105 wkTil et al. (1989)

0, 1.2, 15, 82 mg/kg bw/d70/group

No increase in tumour incidence NS Formaldehyde generated from 95% pure 

paraformaldehyde.Interim sacrifices of 10 rats after 53 and 79 wk.

Wistar rat (F)105 wkTil et al. (1989)

0, 1.8, 21, 109 mg/kg bw/d70/group

No increase in tumour incidence NS Formaldehyde generated from 95% pure 

paraformaldehyde. Interim sacrifices of 10 rats after 53 and 79 wk.

Sprague Dawley (M, F)LifetimeSoffritti et al. (1989)

0 and 2 500 ppm 

Exposure of breeders (18–20/group/sex) and offspring (36–59/group/sex) for 104 wk. Exposure of offspring began on d 13 of gestation.

Leukaemias: Previous and current Working Group 

and other authors (Feron et al., 1990; IARC, 2006) noted concern about study design, significance of tumour findings and laboratory-control incidences. The Working Group also noted that leukaemias included three types, diagnosed as lymphoblastic leukaemias and lymphosarcomas, immunoblastic lymphosarcomas, and other types of leukaemias and haemolymphoreticular sarcomas.Increased incidence of a variety of benign and malignant stomach and intestinal tumours was also reported. The stomach tumours in treated groups represented single occurrences of neoplasm of different sites/cell type fore-stomach/squamous, smooth muscle and glandular stomach epithelium.

Breeders (M): 2/18 (11.1%) vs 0/20 (0%) NSBreeders (F): 2/18 (11.1%) vs 1/20 (5%) NSOffspring (M): 4/36 (11.1%) vs 3/59 (5.1%)

NS

Offspring (F): 0/37 (0%) vs 3/49 (6.1%) NSSmall intestine leiomyosarcoma:Offspring (F): 6/37 (16.2%) vs 0/49 (0%)

P < 0.01

Table 3.1 (continued)
IARC MONOGRAPHS – 100F

416

Species, strain (sex)DurationReference

Dosing regimen,Animals/group at start

Incidence of tumours Significance Comments

Sprague Dawley (M, F)LifetimeSoffritti et al. (1989, 

2002)

0 (control), 0 (15 mg/L methanol control), 10, 50, 100, 500, 1 000, 1 500 mg/L for 104 wk

50/group/sex (100/control group)

Testicular interstitial-cell adenomas:24/50 (1 000 mg/L) vs 6/50 (methanol control)

[P < 0.01] Purity of 99% with 0.3% methanol as 

stabilizer.Concerns by the Working Group about pooling of several types of lymphohaematopoietic tumours. Concern also about interpretation of the results for lymphohaematopoietic tumours due to the numerous and extensive discrepancies in tumour incidences between the first (Soffritti et al., 1989) and second report 

(Soffritti et al., 2002) on results for 

this study. Increased incidence of total malignant tumours in males treated with 1 500 mg/L [

P < 0.01].

Lymphohaematopoietic tumours:Males8/100, 20/50, 8/50, 20/50, 26/50, 24/50, 22/50, 46/50*

[P < 0.01, trend], *[

P < 0.01, vs 

methanol control]

a Nasal cavity tumours were squamous-cell carcinomas.b Nasal cavity tumours (combined) included carcinomas (2), undifferentiated carcinomas or sarcomas (2) or carcinosarcomas (1).c Nasal cavity tumours were polypoid adenomas.d Three squamous-cell carcinomas, 2 polypoid adenomas, and 1 carcinoma in situ.e Nasal cavity tumours were squamous-cell carcinomas except for one adenosquamous carcinoma and one adenocarcinoma at 10 ppm (D) with 28 months of exposure and one 

carcinoma in situ at 10 ppm (D) and one polypoid adenoma at 10 ppm (U) with 3 mo of exposure.

f Nasal cavity tumours were squamous-cell papillomas.

B[a]P, benzo[a]pyrene; d, day or days; h, hour or hours; F, female; M, male; mo, month or months; MNNG, 

N-methylN′-nitroN-nitrosoguanidine; NDEA, 

N-nitrosodiethylamine; NR, 

Table 3.1 (continued)

not reported; NS, not significant; vs, versus; wk, week or weeks
Formaldehyde

4. Other Relevant Data

In IARC Monograph Volume 88 (IARC, 

2006) mechanistic considerations supported a 

role for cytotoxicity and genotoxicity in formaldehyde-induced nasal tissue carcinogenesis. 

With regards to leukaemia, it was unclear to the 

Working Group at the time how this reactive 

compound could penetrate to the bone marrow, 

and no animal model of formaldehyde-induced 

leukaemia was available.

The discussion below focuses on mechanistic 

issues related to the potential causal association 

between formaldehyde inhalation and hematological cancers, and includes considerations 

on the mechanism underlying nasal carcinogenesis in laboratory animals and humans. A 

more detailed review can be found in Volume 88 

(IARC, 2006).

4.1 Absorption, distribution, 

metabolism, and excretion

One-carbon metabolism is central to many 

biological processes, including the biosynthesis 

of purines and thymidine – essential components of nucleic acids –, the biosynthesis of 

certain amino acids, and the demethylation of 

a variety of important biological compounds 

that are central to cell function and survival. 

Formaldehyde is an intermediate in the onecarbon pool and is present in measurable 

concentrations in all metabolically active cells 

and tissues (Heck et al., 1982, 1985; Casanova 

et al., 1988). In aqueous solution, formaldehyde 

is rapidly converted to its diol form, methanediol 

(formaldehyde hydrate, CH2

(OH)2, methylene 

glycol), which enters in a dynamic equilibrium 

with formaldehyde. The concentration of the diol 

and that of formaldehyde depend on the precise 

conditions (temperature, pH, formaldehyde 

concentration) under which the reaction occurs 

(Walker, 1964). Importantly, methanediol, with 

a molecular weight of only 48, can readily penetrate into tissue (Fox et al., 1985). Thus, formaldehyde may reach the bone-marrow through the 

blood as methanediol, where it equilibrates again 

to reactive formaldehyde. Further investigation 

of this equilibrium in living biological systems 

is warranted.

The absorption of formaldehyde occurs 

readily in the upper respiratory tract (Casanova 

et al., 1991; Kimbell et al., 2001a, b). Once 

inhaled, formaldehyde can react directly with 

mucus or with macromolecular cellular components including proteins and nucleic acids; it 

can be incorporated into biological molecules 

through folate-dependent enzymatic processes; 

it can be oxidized to formic acid or to carbon 

dioxide through enzymatic processes dependent 

on formaldehyde dehydrogenase, aldehyde dehydrogenase and, in limited situations, catalase 

(Hedberg et al., 2002), or itcan be exhaled. It 

has been estimated that as much as 22–42% of 

inhaled formaldehyde may be removed by mucus 

flow (Schlosser, 1999).

Formaldehyde reacts readily and reversibly 

with amino groups to form Schiff bases, and 

with sulfhydryl groups resulting in the formation of S-hydroxymethylglutathione, which is 

oxidized by alcohol dehydrogenase-3 (ADH3) 

to S-formylgluthahione. The latter is further 

metabolized by S-formylgluthione hydrolase to 

generate formate and gluthione. The formate 

can also be formed non-enzymatically (Hedberg 

et al., 2002). Incubation of 0.1–5.0 mM formaldehyde with reduced glutathione in solution 

followed by addition to deoxyguanosine or to calfthymus DNA leads to the formation of the relatively stable adduct S-[1-(N2

-deoxyguanosinyl)

methyl]glutathione (Lu et al., 2009). This adduct 

may form endogenously, as both formaldehyde 

and reduced glutathione are present in reasonably high concentrations within cells. It may 

also serve as a biomarker to study the penetration of inhaled radio-labelled formaldehyde, 

to distinguish endogenous from exogenous 

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IARC MONOGRAPHS – 100F

formaldehyde-derived adducts. Whether this 

could also be a mechanism by which inhaled 

formaldehyde could lead to bone-marrow toxicity 

has not been studied.

Red blood cells have relatively high levels of 

enzymes that rapidly metabolize formaldehyde. 

The concentration of formaldehyde in the blood 

of six human volunteers did not change immediately after exposure to 1.9 ppm [2.34 mg/m3

] 

formaldehyde for 40 minute (Heck et al., 1985), 

and no change in formic acid concentration 

was observed in the urine of medical students 

over a three-week period during which they 

were exposed to air concentrations <  0.5 ppm 

[0.62 mg/m3

] (Gottschling et al., 1984). No statistically significant change in the concentration of 

formaldehyde in blood was found after inhalation of this substance at 1.9 ppm [2.34 mg/m3

] for 

40 minute by six human volunteers; at 14.4 ppm 

[17.8 mg/m3

] for two hours in rats (Heck et al.,

1985); and at 6 ppm [7.4 mg/m3

] for six hours/

day, five days per week, for four weeks in Rhesus 

monkeys (Casanova et al., 1988). Blood was 

drawn approximately 7 min and 45 hours after 

the end of the exposure period, from monkeys 

whose blood levels were 1.84  ±  0.15 μg/g and 

2.04 ± 0.40 μg/g, respectively. However, there are 

methodological concerns with these studies. In 

the monkey study three animals were used to 

determine control levels and three others were 

exposed to formaldehyde. The mean levels were 

then compared. It would have been better if the 

monkeys had served as their own control. A 

similar lack of change in formaldehyde levels was 

reported in rats (2.25 ± 0.07 vs 2.24 ± 0.07 μg/g 

blood) and humans (2.77 ± 0.28 vs 2.61 ± 0.14 μg/g 

blood; approximately 0.1 mM) exposed for short 

periods to 14.4 and 1.9 ppm, respectively (Heck 

et al., 1985; Casanova et al., 1988; IARC, 2006). 

[The Working Group noted that, given the short 

half-life for formaldehyde observed in rodents, 

the time from end-of-exposure to sampling in 

monkeys and in humans was likely too long; this 

could not be evaluated for rats].

Studies of the uptake of radio-labelled formaldehyde by inhalation, ingestion and through the 

skin do not provide information that would help 

to determine whether unreacted formaldehyde 

reaches the bone marrow, because it is rapidly 

taken up in the one-carbon pool and incorporated in macromolecules. There was no evidence 

of the formation of formaldehyde-specific DNA–

protein crosslinks in the bone marrow of Rhesus 

monkeys exposed for six hours to 0.7, 2.0 and 6.0 

ppm formaldehyde (Heck & Casanova, 2004), or 

in rats, including glutathione (GSH)-depleted 

rats, exposed to concentrations of formaldehyde up to 10 ppm (Casanova-Schmitz et al.,

1984; Casanova & Heck, 1987). The formation of 

formaldehyde-DNA adducts was demonstrated 

in lymphocytes of smokers (Wang et al., 2009). 

In this study, liquid chromatography-electrospray ionization-tandem mass spectrometry was 

used to quantify the adduct N6

-hydroxymethyldeoxyadenosine (N6

-HOMe-dAdo) in leukocyteDNA samples from 32 smokers (≥ 10 cigarettes 

per day) and 30 non-smokers. This adduct would 

be expected to be formed upon exposure to 

formaldehyde. N6

-HOMe-dAdo was detected 

in 29 of the 32 samples from smokers, but in 

only 7 of the 30 samples from non-smokers 

(P < 0.001). These findings would support a role 

for inhaled formaldehyde in causing the DNA 

adducts that may ultimately lead to smokingassociated leukaemia. The authors caution that 

the observed adducts may result from cigarettesmoke components other than formaldehyde 

– such as 4-(methylnitrosamino)-1-(3-pyridyl)-

1-butanone (NNK) or nicotine, which may be 

metabolized to formaldehyde within the cell – 

or from other sources, rather than reflecting the 

actual penetration of inhaled formaldehyde to 

lymphocytes.

Rietbrock (1965) reported that the half-life in 

plasma of formaldehyde injected intravenously 

in the rat was about one minute. [Assuming a 

similar half-life of formaldehyde in humans, this 

would be sufficient time for inhaled formaldehyde 

418
Formaldehyde

to reach the blood and circulate to the bone 

marrow in humans].

4.2 Toxic effects

Formaldehyde produces irritation of the 

nose and pharynx in humans and laboratory 

animals under a variety of circumstances. There 

appears to be a large inter-individual variation 

in the human response to the irritating effects 

of formaldehyde. Under controlled exposure 

conditions, symptoms of irritation were noted 

by healthy individuals exposed to formaldehyde 

concentrations of 2–3 ppm during periods that 

varied between 40 minute and three hours (for 

details, see Table 30 in IARC Monograph Volume 

88 (IARC, 2006)).

Formaldehyde is a known cause of allergic 

contact dermatitis and, somewhat more controversial, of occupational asthma. Nasal biopsies 

of workers chronically exposed to formaldehyde 

showed chronic inflammation, loss of cilia, mild 

dysplasia, hyperplasia and squamous metaplasia, 

although the latter finding has been inconsistent 

and may have been confounded by other exposures, such as to wood dust (IARC, 2006).

The cytotoxicity of formaldehyde has been 

confirmed in numerous in-vitro systems. 

Irritation of the nasal and upper respiratory tract 

is also noted in animal studies. Dose-dependent 

pathological findings include inflammation, 

hyperplasia, degenerative changes, necrosis and 

squamous metaplasia.

Recently, a finding relevant to the possible 

involvement of formaldehyde in leukaemogenesis was reported by Zhang et al. (2010). 

Their study showed that colony formation by 

colony-forming unit-granulocyte-macrophage 

(CFU-GM) progenitor cells is inhibited in cell 

cultures exposed to formaldehyde at toxicologically relevant concentrations. Furthermore, 

colony formation by the more primitive 

CFU-granulocyte- erythrocyte-monocytemegakaryocyte (CFU-GEMM) progenitors, 

which give rise to formation of all myeloid cells, 

showed a linear negative dose–response when 

treated with formaldehyde. These effects were 

observed at formaldehyde concentrations of 

100–200 μM [3–6 μg/mL], which are toxicologically relevant since background levels of formaldehyde in human blood have been reported to 

be 50–100 μM [1.5–3 μg/mL] (Heck et al., 1985; 

Casanova et al., 1988). Because the CFU-GEMM 

multipotent myeloid progenitor cells and the 

pluripotent stem cells are the target cells for 

leukaemogenesis and are converted to leukaemic 

stem cells in acute myeloid leukaemia, the finding 

that formaldehyde damages these cells in vitro

adds some weight to the notion that it may be 

associated with myeloid leukaemia.

4.3 Genetic and related effects

The genotoxicity of formaldehyde was thoroughly reviewed in IARC Monograph Volume 88 

(IARC, 2006). Genotoxicity has been observed in 

vitro in many systems with multiple endpoints.

4.3.1 Humans

Micronucleus formation has been repeatedly reported to occur in cells of the nasal and 

oral mucosa of formaldehyde-exposed humans. 

The outcome of studies on induction of micronuclei, sister chromatid exchange and chromosomal aberrations in the lymphocytes of exposed 

humans – which is pertinent to the question 

concerning the potential of formaldehyde to 

cause lympho-haematopoietic cancer – has been 

less consistent (see Table 4.1).

DNA–protein crosslinks in circulating 

white blood cells were found to be higher in 12 

workers exposed to formaldehyde in an anatomy 

department and a pathology institute than in 

eight controls (P  =  0.03) (Shaham et al., 1996). 

The number of crosslinks tended to be higher in 

workers who had been exposed longer (exposure 

duration, 2–31 years). Smoking had no effect. In a 

419
IARC MONOGRAPHS – 100F

420Table 4.1 Cytogenetic studies on formaldehyde–exposed humans

Reference Description of exposed 

and controls

Exposure levels Cytogenetic/genotoxic endpoint Response in exposed Response in controls Comments

Costa et al. (2008), Portugal

Workers in an anatomypathology laboratory (n = 30) Controls non-exposed (n = 30)

0.44 ± 0.08 ppm(range 0.04–1.58)

Micronucleus formation in lymphocytes (MN/1000 cells)

5.47 ± 0.76 3.27 ± 0.69

P = 0.003

Sister-chromatid exchange(SCE) 6.13 ± 0.29 4.49 ± 0.16

P < 0.05

DNA-breakage (comet tail length, μm) in lymphocytes

60.00 ± 2.31 41.85 ± 1.97

P < 0.05

Pala et al. 

(2008), Italy

Laboratory workers (n = 36) in a cancer research institute

Exposure range:4.9–268.7 μg/m3

Low: < 26 μg/m3

High: ≥ 26 μg/m3

High: Low:

Micronucleus formation (MN) MN: 0.31 ± 0.17 MN: 0.26 ± 0.24

Chromosomal aberrations (CA) CA: 2.22 ± 1.27 CA: 2.95 ± 1.79

SCE in lymphocytes SCE: 5.06 ± 0.76 SCE: 6.57 ± 1.38

Iarmarcovai et al. (2007), 

France

Pathologists/anatomists (n = 18)Controls (n = 18)

2.3 ppm(range 0.4–7 ppm)

MN in lymphocytes (MN/1000 cells)

21.0 ± 12.6 14.4 ± 8.1

P < 0.01

Yu et al. (2005), the People’s Republic of China

Workers (n = 151; low-exposed, 62; highexposed, 89) in two plywood factories; 112 non-exposed controls.

TWA: 0.10–7.88 mg/m3 (< 0.01 mg/m3 in 

controls)

MN in lymphocytes (MN/1000 cells)

High exp. 6.5 ± 3.6Low exp. 4.1 ± 2.5

2.7 ± 1.3

P < 0.05

DNA-breakage (comet tail length, μm) in lymphocytes

High exp., 12.6(95% CI: 11.8–13.4)Low exp., 11.3(95% CI: 10.1–12.5)

6.8 (95%CI: 6.1–7.6)

P < 0.05

Ye et al. (2005), the People’s Republic of China

Workers (n = 18; all non-smokers) in a formaldehyde factory (mean exposure duration, 8.5 yrs), and waiters (n = 16; all non-smokers) exposed to formaldehyde for 12 wk in a newly fitted ballroom. Controls were 23 students (non-smokers)

Factory: 8-h TWA, 0.99 ± 0.29 mg/m3, 

with peak exposure 1.69 mg/m3

.

Ballroom: 5-h TWA0.11 ± 0.07 mg/m3, 

with peak exposure 0.3 mg/m3

Control: 0.01 ± 0.003 mg/m3, with peak 0.015 

mg/m3

MN in nasal mucosa (MN/1000 cells) of factory workers

2.70 ± 1.50 1.25 ± 0.65

P < 0.05

SCE in lymphocytes of factory workers

8.24 ± 0.89 6.38 ± 0.41

P < 0.05

No effects in ballroom waiters
Formaldehyde

421

Reference Description of exposed 

and controls

Exposure levels Cytogenetic/genotoxic endpoint Response in exposed Response in controls Comments

Shaham et al. (2002), Israel

Workers (n = 90) in hospital pathology departments; controls were 52 unexposed workers from the same hospitals. Average duration of exposure 15.4 yrs (range, 1–39)

Low:

0.4 ppm (0.04–1.7)High:2.24 ppm (0.72–5.6)

SCE in lymphocytes (mean number of SCE per chromosome)

0.27 ± 0.003 0.19 ± 0.002

P < 0.01

Burgaz et al. 

(2002), Turkey

a) Workers (n = 22) in a shoe factory

n-hexane, toluene, methyl ethyl ketone

MN in buccal cells (MN/1000 cells)

a) 0.62 ± 0.45

P < 0.05

b) Pathologists (n = 28), anatomy laboratories

2–4 ppm formaldehyde

b) 0.71 ± 0.56

P < 0.05

c) Controls (n = 18): university staff

none c) 0.33 ± 0.30

Burgaz et al. 

(2001), Turkey

Workers (n = 23) in pathology and anatomy laboratories, and 25 nonexposed controls

Air concentration of formaldehyde in the breathing zone 2–4 ppm.

MN in nasal mucosa (MN/1000 cells; mean ± SD).

1.01 ± 0.62 0.61 ± 0.27

P < 0.01

Suruda et al. 

(1993), USA

Students (n = 29) taking 85-d course in embalming; average number of embalmings, 6.9; total number 144.

Average air concentration of formaldehyde: 1.4 ppm, range 0.15–4.3mean duration of embalming 125 minute with peak exposures > 4 ppm.

MN per 1 000 cells: MN after course MN before course

- buccal cells 0.60 ± 1.27 0.046 ± 0.17

P < 0.05

- nasal cavity 0.50 ± 0.67 0.41 ± 0.52 NS- lymphocytes 6.36 ± 2.03 4.95 ± 1.72

P < 0.05

SCE in lymphocytes 7.14 ± 0.89 7.72 ± 1.26

P = 0.01 (decrease in SCE)

Ying et al. 

(1999), China

Students (n = 23; nonsmokers) in 8-wk (3h x 3 times weekly) anatomy class.

TWA 0.51 ± 0.30 mg/m3, with peak 

exposure 1.28Background level in dormitories 0.012 ± 0.0025 mg/m3

SCE after course SCE before course

SCE in lymphocytes 6.61 ± 0.79 6.38 ± 0.41 NS

Table 4.1 (continued)
IARC MONOGRAPHS – 100F

422

Reference Description of exposed 

and controls

Exposure levels Cytogenetic/genotoxic endpoint Response in exposed Response in controls Comments

He et al. (1998), 

China

Students (n = 13; nonsmokers) in 12-wk (10h 

per wk) anatomy class. Ten other students (nonsmokers) served as nonexposed controls.

Average air concentration of formaldehyde: 2.37 ppm (3.17 mg/m3

)

MN per 1 000 cells in lymphocytes

6.38 ± 2.50 3.15 ± 1.46

P < 0.01

CA in lymphocytes 5.92 ± 2.40 3.40 ± 1.57

P < 0.01

SCE in lymphocytes 5.91 ± 0.71 5.26 ± 0.51

P < 0.05

Ying et al. 

(1997), China

Students (n = 25; nonsmokers) in 8-wk (3h x 3 times weekly) anatomy class.

TWA 0.51 ± 0.30 mg/m3, 

with peak exposure 1.28Background level in dormitories 0.012 ± 0.0025 mg/m3

MN per 1 000 cells in- nasal exfoliated cells 3.84 ± 1.48 1.20 ± 0.67

P < 0.001

- oral mucosa cells 0.86 ± 0.56 0.57 ± 0.32

P < 0.01

- lymphocytes 1.11 ± 0.54 0.91 ± 0.39 n.s.

TitenkoHolland et al. 

(1996), USA

Students (n = 28) taking a 90-d embalming class; average number of embalmings, 6.9; total number 144.

Accumulated dose over 90 d: 4.3–26.4 ppmMaximum peak exposure: 2.86 ppm

MN per 1 000 cells with centromere-specific probes (FISH) in:

MN after class MN before class [between 

parentheses: values for centromerenegative MN]

- buccal cells 2.0 ± 2.0 (0.9 ± 1.1) 0.6 ± 0.5 (0.1 ± 0.2)

P = 0.007 (P = 0.005)

- nasal cells 2.5 ± 1.3 (1.0 ± 0.6) 2.0 ± 1.3 (0.5 ± 0.5)

P = 0.20 (P = 0.03)

Table 4.1 (continued)
Formaldehyde

423

Reference Description of exposed 

and controls

Exposure levels Cytogenetic/genotoxic endpoint Response in exposed Response in controls Comments

Dobiás et al. (1988), Czechoslovakia

- Schoolchildren (n = 20 children) in school building constructed with wood-particle boards- Control group (n = 17 children) in brick school building in the same area- Control group in brick school building elsewhere

Formaldehyde concentration in air:1984: 317.0 μg/m3

1985: 130.0 μg/m3

1986: 36.5 μg/m3

CA in lymphocytes (per 100 cells) in lymphocytes

1984: 7 1984: 4.21985: 4.2 NR1986: NR NR

The frequency of chromosomal aberrations is stated ‘normal’ in 1986 but the value is not given

Building was cleaned in ‘85, ‘86

Percentage of aberrant cells 1984: 4.71 ± 2.09 1984: 1.37 ± 0.87 P = 0.005

1985: 2.82 ± 1.64 1985: 1.4 ± 0.791986: 2.06 ± 1.51 NR

Bauchinger & Schmid (1985), Germany

Workers (n = 20; 6 smokers) in a paper factory, where formaldehyde was used for impregnating the paper. Duration of exposure 2–30 yrs, average 14.5 ± 7.2 yrs. Controls were 20 nonexposed workers (13 smokers) elsewhere in the factory

Formaldehyde exposure, < 0.2 ppm Peak during repair and cleaning, 3 ppm

CA in lymphocytes (dicentrics, rings) per 100 cellsSCE/cell ± SE

0.13 ± 0.05 0.05 ± 0.028.87 ± 0.24 9.53 ± 0.35 NS

Table 4.1 (continued)

CA, chromosomal abberations; d, day or days; h, hour or hours; min, minute or minutes; MN, micronuclei; NR, not reported; NS, not significant; SCE, sister chromatid exchange; TWA, time-weighted average concentration
IARC MONOGRAPHS – 100F

subsequent study, Shaham et al. (2003) reported 

an increase in the number of DNA–protein 

crosslinks in lymphocytes and in serum concentrations of the p53 protein in hospital pathologydepartment workers. The exposed subjects were 

assigned to a high-exposure subgroup (mean 

formaldehyde concentration in air, 2.24 ppm) 

and a low-exposure subgroup (mean, 0.4 ppm), 

based on personal sampling and field sampling 

for 15-minute periods on typical working days. 

The control group consisted of personnel of 

the administrative sections in the hospital. The 

amount of protein–cross-linked DNA was statistically significantly higher in the exposed group 

than in the controls (0.20 vs 0.14; these values 

are the ratios between protein-bound DNA – 

precipitable with sodium dodecyl sulfate – and 

total DNA) after controlling for age, smoking 

and other factors. Very little difference in DNA–

protein crosslink levels was observed between 

the high- and low-exposure groups (0.20 vs

0.19); or between workers with > 16 years or < 16 

years of exposure (0.20 vs 0.19). The percentage 

of formaldehyde-exposed male workers who had 

pantropic p53-protein (wild-type plus mutant 

p53) concentrations in serum higher than 

150 pg/ml was statistically significantly greater 

than in the control group (54.8% vs 36.5%, 

P < 0.05; this difference was not seen in female 

workers). Formaldehyde-exposed workers with 

DNA–protein crosslink levels above the median 

had a significantly greater likelihood of having 

p53 concentrations in serum above 150 pg/ml. 

[The Working Group noted that the rationale 

for using a p53-protein level of 150 pg/ml as a 

cut-point was based upon previous experience 

with this assay; no reason is given for using 16 

years as the cut-point between longer/shorter 

exposure. Questions have also been raised about 

the persistence of DNA–protein crosslinks, 

which are thought to be rapidly repaired within 

the cell (Schmid & Speit, 2007)]. In an earlier 

study, Casanova-Schmitz et al. (1984) failed 

to observe DNA–protein crosslinks in bone 

marrow of Fischer-344 rats exposed to [14C]- and 

[

3

H]-formaldehyde.

Compared with matched controls, pathology/

anatomy workers from five hospitals, who 

were exposed to mean formaldehyde concentrations of 2.0 ppm (range, <  0.1 to 20.4 ppm) 

during 15 minute, or to 0.1 ppm (range < 0.1 to 

0.7 ppm) during 8 hours, showed a statistically 

significant increase in bi-nucleated cells and 

in mono-centromeric micronucleus formation 

in a cytokinesis-blocked micronucleus assay 

combined with fluorescence in situ hybridization 

(FISH) (Orsière et al., 2006).

A higher frequency of micronuclei was found 

in exfoliated nasal and oral cells of students 

with short-term exposure (3  hours per day; 

3  days per week, for 8 weeks) to an average of 

0.508  ±  0.299 mg/m3

 formaldehyde, compared 

with controls (Ying et al., 1997, 1999). No increase 

in micronucleus formation or in the level of 

sister chromatid exchange (SCE) was observed 

in lymphocytes. Ye et al. (2005) reported a 

comparative analysis of 18 workers involved 

for various periods (mean, 8.5  years; range, 

1–15 years) in a formaldehyde-manufacturing 

process, 16 waiters exposed for 12 weeks to an 

indoor source of formaldehyde during interior 

renovations, and a control group of 23 students; 

all were non-smokers. Average formaldehyde 

exposure-concentrations were 0.011 mg/m3

 for 

the student controls; 0.107 mg/m3

 for the waiters; 

and 0.99 mg/m3

 for the formaldehyde-plant 

workers. There was a statistically significantly 

higher frequency of micronuclei in nasal mucosal 

cells and of SCE in peripheral lymphocytes in 

the workers at the formaldehyde-manufacturing 

plant, but not in the waiters, although both groups 

were exposed to formaldehyde at comparable 

concentrations (Table  4.1). The result is in line 

with the much longer exposure duration for the 

plant workers. The same authors (Ye et al., 2005) 

reported an increase in B-cells and changes in 

the ratios between lymphocyte subsets, similar 

to those reported by Madison et al. (1991) in an 

424
Formaldehyde

Alaskan community subject to acute formaldehyde exposure (estimated at 2–5 ppm) for a 

few days. Blood analyses were done three years 

after the accident. Total white blood cell counts 

and total lymphocyte counts did not differ from 

those in the control community in Alaska, also 

measured three years later (Madison et al., 1991).

An increase in SCE and other genotoxic 

effects were observed in the lymphocytes of 

workers with long-term exposure to formaldehyde (Costa et al., 2008). Thirty workers from 

four pathology/anatomy hospital units and 30 

matched controls were included in the study. 

Compared with the control group, statistically 

significant effects were seen in SCE (6.13 ± 0.29 

vs 4.49 ± 0.16 SCE/cell, P < 0.05), micronucleus 

frequency (in 1000 bi-nucleated cells: 5.47 ± 0.76 

‰ vs 3.27 ± 0.69 ‰, P = 0.003) and tail length in 

the comet assay (60.0 ± 2.31 μm vs 41.85 ± 1.97 

μm, P < 0.05). A statistically significant positive 

correlation was found between formaldehyde 

exposure levels and micronucleus frequency and 

tail length. The mean formaldehyde exposure 

was 0.44 ppm (range, 0.04–1.58 ppm). None of 

the observed effects were related to the duration 

of exposure.

No genotoxic effects were observed in a study 

of 36 laboratory workers at a cancer-research 

institute who were exposed to 4.9–268.7 μg/m3

formaldehyde. There was a direct relationship 

between formaldehyde exposure levels and 

the presence of a formaldehyde human serumalbumin (FA-HSA) conjugate. The genotoxic 

endpoints measured were SCE, micronuclei and 

chromosome aberrations, but these did not show 

significantly elevated levels (Pala et al., 2008). 

Although a small study, its strength is its linkage 

to a biological marker of formaldehyde exposure.

Hayes et al. (1997) evaluated O6

-Alkylguanine-DNA–alkyltransferase (AGT) activity 

as a measure of DNA-repair capacity in 

blood lymphocytes of 23 science students in a 

mortuary, before and after a nine-week period 

of classroom exposure to approximately 1.5 ppm 

formaldehyde. A statistically significant finding 

was that more students had a reduction in AGT 

activity than an increase. There was no clear link 

between the extent of exposure to formaldehyde 

and AGT activity.

Zhang et al. (2010) cultured myeloid progenitor cells from the peripheral blood of formaldehyde-exposed workers and controls and measured 

leukaemia-specific chromosomal changes. In a 

subset of ten of the most highly exposed subjects 

in their study, monosomy (loss) of chromosome 7 

and trisomy (gain) of chromosome 8 were significantly elevated in the myeloid progenitor cells of 

formaldehyde-exposed workers compared with 

the same phenomena in 12 unexposed controls. 

The loss of chromosome 7 and gain of chromosome 8 were examined because they are among 

the most frequent cytogenetic changes observed 

in myeloid leukaemia and myelodysplastic 

syndromes; these events have been shown to be 

affected by exposure to the established human 

leukemogen, benzene. [The Working Group 

noted that the study is small and needs to be 

replicated].

4.3.2 Experimental systems

(a) In-vivo studies (laboratory animals)

Studies on a variety of genotoxic endpoints 

in laboratory animals inhaling formaldehyde 

have generally shown effects in the nasal tissues 

of these animals (IARC, 2006). Much less 

consistent have been the findings of genotoxic 

effects in the blood lymphocytes from exposed 

animals. Among the recent studies, Im et al.

(2006) reported genotoxicity based on a positive 

result in the comet assay in the lymphocytes of 

rats inhaling 5 or 10 ppm formaldehyde for two 

weeks, six hours/day, five days/week. In contrast, 

in a review of their own work and of the literature, Speit et al. (2009) concluded that there was 

no evidence of systemic genotoxic effects in laboratory animals inhaling formaldehyde. Their 

own negative studies in this review focused on 

425
IARC MONOGRAPHS – 100F

lymphocyte genotoxicity, measured as micronuclei, SCE, and DNA-breakage – the latter determined with a sensitive form of the comet assay 

– in rats exposed for four weeks (six hours/day, 

five days/week) to formaldehyde concentrations 

of 0.5, 1, 2, 6, 10 and 15 ppm.

More recently, DNA strand-breaks were 

induced by formaldehyde in vivo, in mouse liver 

(maternal and fetal), and in lung cells in the rat 

(Wang & Liu, 2006; Sul et al., 2007).

(b) In-vitro studies

The spectrum of mutations related to exposure 

to formaldehyde in vitro and in vivo was presented 

and discussed in IARC Monograph Volume 88 

(IARC, 2006). In-vitro studies since then have 

expanded the wide range of potential mutagenic 

mechanisms, to include the hydroxymethylation of DNA and DNA-microsatellite instability 

(Zhong & Que Hee, 2004; Wang et al., 2007).

The evidence of formaldehyde-induced 

mutations in various experimental systems 

is consistent, encompassing both clastogenic 

effects and direct DNA mutation. Formaldehyde 

showed mutagenic potential in several bacterial 

systems, both with and without S9 activation. 

Formaldehyde induced deletions, point mutations, insertions, and cell transformation in 

in-vitro assays with mammalian cells (IARC, 

2006).

Formaldehyde-induced DNA strand-breaks 

(SSB) have been demonstrated in several 

mammalian cell systems, including hepatocytes, lymphosarcoma cells, and epithelial cells 

from the rat, leukaemia L1210 cells from the 

mouse, and lung/bronchial epithelial cells, skin 

fibroblasts, keratinocytes, and peripheral blood 

lymphocytes from humans (IARC, 2006).

Chromosomal aberrations, micronuclei and 

SCE were all increased in vitro in numerous 

rodent and human primary cells and cell lines 

treated with formaldehyde (IARC, 2006). 

Consistent with these findings, more recent 

data show increased numbers of chromosomal 

aberrations in Syrian hamster embryo cells, and 

chromosomal aberrations and SCE in Chinese 

hamster ovary and embryo cells (Hikiba et al.,

2005, Hagiwara et al., 2006; Lorenti Garcia et al.,

2009).

Further evidence of formaldehyde-induced 

micronucleus formation was obtained in studies 

with human lymphocytes isolated from wholeblood cultures exposed in vitro to formaldehyde, 

44 hours after the start of the culture (Schmid 

& Speit, 2007). Both micronuclei and SCE were 

induced upon in-vitro treatment of Chinese 

hamster V79 lung epithelial cells with formaldehyde (Speit et al., 2007). In a recent study, 

SCE was induced in A549 human lung cells and 

V79 Chinese hamster cells following incubation 

with 0.1 mM [3 μg/mL] or higher concentrations of formaldehyde. One hour after the addition of the agent to the A549 cells, the culture 

medium still retained the capacity to produce 

SCE in non-exposed V79 cells, suggesting that 

genotoxicity persists despite the high reactivity 

of formaldehyde with macromolecules in the 

culture medium (Neuss & Speit, 2008). When the 

formaldehyde-exposed A549 cells were washed 

and then suspended in fresh culture medium 

containing the V79 cells, SCE formation was 

not observed in the latter. [The authors present 

no evidence that it is formaldehyde itself that 

persists, rather than a formaldehyde product 

that is responsible for genotoxicity. The Working 

Group noted that there is no reason to preclude 

the transfer of formaldehyde from cell to cell].

Formaldehyde has also been reported to 

interfere with DNA repair. A recent finding that 

chicken DT40 cells deficient in the FANC/BRCA 

(Fanconi’s anaemia complementation groups/

breast cancer A) pathway are hypersensitive to 

formaldehyde in plasma, is consistent with a 

role for this pathway in repairing DNA–protein 

cross-links caused by formaldehyde. The DT40 

mutants were also more sensitive to acetaldehyde, 

but not to acrolein and other aldehydes (Ridpath 

et al., 2007). Endogenous formaldehyde may be 

426
Formaldehyde

important in producing leukaemia in patients 

with Fanconi’s anaemia, a genetic disorder that 

is characterized by progressive pancytopenia. 

DT40 cells with deficient repair mechanisms 

have also been shown to be more sensitive to 

other cross-linking agents such as cisplatin, a 

myelotoxic chemotherapeutic agent that leads to 

pancytopenia and acute myelogenous leukaemia 

(AML) (Nojima et al., 2005).

4.4 Mechanistic considerations

4.4.1 Cancer of the nasopharynx and nasal 

sinuses

Mechanistic evidence supporting a causal 

relation between inhalation of formaldehyde and 

induction of cancer of the nasopharynx and nasal 

sinuses is based on the chemical reactivity of 

formaldehyde in producing DNA–protein crosslinks, and its genotoxicity in vitro and in vivo, 

including in the nasal cells of exposed humans. 

Computational fluid-dynamic models of formaldehyde in the nasal passages of rats, monkeys 

and humans have generally been accurate in 

predicting the area in the nose with the highest 

number of DNA–protein crosslinks (Georgieva 

et al., 2003). Local effects in the nasal passages, 

genotoxicity, and cell-proliferation rate appear 

to be the major determinants of nasal carcinogenicity after exposure to formaldehyde.

4.4.2 Leukaemia

The findings reviewed in IARC Monograph

Volume 88 (IARC, 2006) pertaining to a potential mechanism for formaldehyde-induced 

leukaemogenesis were summarized as follows: 

“Based on the data available at this time, it was 

not possible to identify a mechanism for the 

induction of myeloid leukaemia in humans.” 

The Working Group further stated that “It is 

possible that formaldehyde itself can reach the 

bone marrow following inhalation, although the 

evidence is inconsistent.” Since that time, Zhang 

et al. (2009), reviewed potential pathways by 

which formaldehyde could act as a leukaemogen. 

Three mechanisms were suggested:

•	 by damaging stem cells in the bone marrow directly, as most other leukaemogens 

do;

•	 by damaging haematopoietic stem/progenitor cells circulating in the peripheral 

blood and

•	 by damaging the primitive pluri-potent 

stem cells present within the nasal turbinates and/or olfactory mucosa.

This subject was reviewed by Heck & Casanova 

(2004), Pyatt et al. (2008), and Goldstein (2011).

(a) Studies in animals

Studies of bone marrow cells in formaldehyde-exposed animals have been inconsistent. 

Kitaeva et al. (1990) described clastogenic and 

cytogenetic effects in the bone marrow of rats 

inhaling 0.5 mg/m3

 or 1.5 mg/m3 of formaldehyde during four hours/day for four months. In 

contrast, Dallas et al. (1992) found no evidence 

of cytogenetic abnormalities in the bone marrow 

of rats exposed to 0.5, 3 or 15 ppm [0.62, 3.7 

or 18.45 mg/m3

] formaldehyde for six hours/

day, five days per week, for one or eight weeks. 

Mice that received up to 25 mg/kg bw formaldehyde in two intra-peritoneal injections within 

24 hours showed no increase in chromosomal 

aberrations or micronuclei in the femoral bone 

marrow (Natarajan et al., 1983). As described in 

section 4.1 above, no increase in formaldehydespecific DNA–protein cross-links was observed 

in the bone marrow of Rhesus monkeys or rats 

under various experimental conditions (Heck & 

Casanova, 2004).

427
IARC MONOGRAPHS – 100F

(b) Considerations of formaldehyde as a 

leukaemogen in relation to other known 

myeloleukaemogens

Known myeloid leukaemogens in humans 

include benzene, ionizing radiation and a variety 

of chemotherapeutic anti-neoplastic agents, all of 

which give rise to pancytopenia. There is evidence 

that for each of these myeloleukaemogens, pancytopenia is caused by genotoxic damage leading to 

destruction of primitive progenitor cells in the 

bone marrow. These cells are responsible for the 

formation of red blood cells, white blood cells 

and platelets, and they are the same progenitor 

cells in which mutations and clonal expansion 

leads to myeloid leukaemia.

In view of the wide variety of genotoxic 

mechanisms shown by the diverse agents that 

have pancytopenia and myeloleukaemogenesis 

in common, it could be anticipated that genotoxic 

effects of formaldehyde on myeloid progenitor 

cells would also result in pancytopenia.

Pancytopenia has not been among the haematological findings in experiments with laboratory animals exposed to relatively high doses of 

formaldehyde, including classic long-term safety 

assessment studies. An increase in haemoglobin 

and monocytes and a decrease in lymphocytes 

were observed in rats receiving 0, 20, 40, or 

80 mg/kg bw formaldehyde by gastric intubation 

on five days/week for four weeks. Lymph-node 

weights were increased but no change in lymphnode cellularity was observed (Vargová et al.,

1993). In one long-term study there was actually a 

statistically significant increase in bone-marrow 

hyperplasia in rats exposed to formaldehyde at 15 

ppm (Batelle, 1981), the opposite of what would 

be expected for an agent that has effects similar 

to those of other known myeloleukaemogens.

In contrast to the findings in laboratory 

animals, there has been some evidence suggesting 

a mild pancytopenic effect in humans. A study 

of 50 haemodialysis nurses exposed to formaldehyde compared with 71 non-exposed ward nurses 

from five different hospitals comprised measurements of formaldehyde and two different blood 

counts recorded one a year apart. Both personal 

and ambient measurements of formaldehyde 

varied widely, from non-detectable up to 2.8 

ppm. Average duration of employment was three 

years for both groups. Symptoms attributable 

to formaldehyde were reported in the exposed 

group. For the second blood count, but not the 

first, there was a statistically significant inverse 

correlation (P < 0.05) between white blood-cell 

count and formaldehyde concentration, as well 

as between white blood-cell count and symptom 

score. No statistically significant correlation was 

observed between formaldehyde concentrations 

or symptoms and platelet or red blood-cell counts. 

The exposed group had a lower white blood-cell 

count than the control group (Kuo et al., 1997). 

[The Working Group noted that absolute data for 

blood counts were not given, nor was the statistical methodology described]

An increase in B-lymphocytes and changes 

in ratios of lymphocyte subsets were noted in 

formaldehyde-plant workers exposed to an 

average of 0.99 mg/m3

 formaldehyde for a mean 

duration of 8.5 years (Ye et al., 2005). Differences 

in the ratios of lymphocyte subsets were also 

observed in an Alaskan community with an 

acute formaldehyde exposure (2–5 ppm for a 

few days), but no differences with the control 

community were seen in total white blood-cell 

counts or lymphocyte counts (Madison et al.,

1991). Likewise, no significant differences in 

blood counts were found in a comparative study 

of students of two schools, in one of which there 

were elevated concentrations of formaldehyde 

and toluene (Vozenílková et al., 1991).

In a review of formaldehyde exposure in the 

People’s Republic of China, Tang et al. (2009)

mentioned eight studies on formaldehydeexposed individuals. Lower white blood-cell 

counts were observed in the six studies that 

provided information on this point, four of 

which were statistically significant; platelet 

428
Formaldehyde

counts were decreased in all three studies where 

this was measured, two of which were statistically significant; and haemoglobin was lower 

in one of the three studies for which data were 

reported. The one study that found lower than 

normal values for each blood count – consistent 

with a pancytopenic effect – was specifically 

the study with the lowest exposure to formaldehyde (0.022–0.044 mg/m3

), although the largest 

cohort. [From the Table in the Tang et al. (2009)

paper, it is not clear whether these are the same 

individuals or separate individuals who have each 

of the lower counts, i.e. how many were pancytopenic. There also is no information about the 

usual confounders, including gender and age].

The finding of statistically significant, 

moderately lower blood counts in formaldehyde-exposed Chinese workers as compared to a 

matched control group would be consistent with 

formaldehyde-induced damage to either circulating haematopoietic precursor cells, or with a 

direct effect on such cells within the bone marrow 

(Zhang et al., 2010). In this study the 43 exposed 

workers at a formaldehyde-melamine producing 

factory or a factory in which formaldehyde-melamine resins were used to produce utensils, were 

exposed to a median of 1.28 ppm formaldehyde 

(10–90%, range 0.63–2.51 ppm; 8-hour timeweighted average), compared with a median level, 

in a matched control group of 51 individuals, of 

0.026 ppm (10–90%, range 0.0085–0.026 ppm). 

Absolute blood counts were only given for total 

white blood-cell counts: in controls, mean (SD) 

6269 (1452) cells per μl blood; and in exposed: 

mean 5422 (1529) cells per μl blood, P = 0.0016. 

Data for the other blood counts are presented 

in a bar chart, and for red blood cells, platelets, 

granulocytes and lymphocytes there are small 

but statistically significant decreases that appear 

to fall within the clinical range of normal. Also 

of note is a statistically significant increase in 

the mean corpuscular volume (MCV) of red 

blood cells. The MCV tends to be increased in 

myelodysplastic conditions. The study appeared 

to have adequately taken into account possible 

confounders such as alcoholism and nutritional 

issues that might cause pancytopenia and an 

increased MCV.

(c) Leukaemogenesis on the basis of reactions 

with myeloid stem cells within the nose

As indicated above, Zhang et al. (2009) have 

suggested that one mechanism of formaldehydeinduced leukaemogenesis might involve reaction of formaldehyde or a reactive formaldehyde 

derivative with myeloid precursors present 

within the nose. This has been questioned on 

two indirect grounds (Goldstein, 2011). Nasal 

tissue does not seem to have been reported as 

a location for chloromas, which are isolated 

collections of myeloid leukaemia cells, despite 

the presence of chloromas in virtually all other 

tissues. Second, known nasal carcinogens, 

including cross-linking agents such as nickel 

and chromium, are not reported to cause an 

increase in acute myelogenous leukaemia. The 

one possible exception is sulfur mustard, a nasal 

carcinogen for which an increase in leukaemia 

(13 deaths observed; 8.51 expected; not statistically significant) was reported by Easton et al.

(1988) in workers producing sulfur mustard gas 

during World War II. However, this agent also 

produces pancytopenia, an outcome that led to 

the development of nitrogen mustard as a chemotherapeutic compound. None of the other known 

human nasal carcinogens has been reported to 

cause pancytopenia.

(d) Formaldehyde and lymphoid cancers

Genotoxicity studies on blood lymphocytes 

from laboratory animals that inhaled formaldehyde have tended to be negative, although 

not consistently so. In comparison, somewhat 

more studies with the lymphocytes of humans 

exposed to formaldehyde have reported genotoxicity, although the findings are also inconsistent. Genotoxicity in circulating lymphocytes 

would be consistent with the possibility that 

429
IARC MONOGRAPHS – 100F

formaldehyde is a cause of lymphatic tumours. 

Particularly at risk would be mucosa-associated 

lymphatic tissue in the nasal area.

The evolution of our understanding of 

lymphohaematopoitetic cancers has led to 

ongoing reclassification of these tumours. There 

is also recognition of their inter-relatedness 

through a common stem cell, and the fact that 

there is a risk for malignant transformation 

during various stages of the differentiation and 

maturation process of the precursor cells. Recent 

evidence suggests that an underlying cytogenetic abnormality in an early precursor cell 

predisposes to subsequent mutations leading to 

a specific haematological cancer. The possibility 

of a mutagenic effect of formaldehyde on circulating lymphocytes or local lymphatic tissue 

cannot be excluded.

4.5 Synthesis

The current data strongly indicate that genotoxicity plays an important role in the carcinogenicity of formaldehyde in nasal tissues in 

humans, and that cellular replication in response 

to formaldehyde-induced cytotoxicity promotes 

the carcinogenic response. Three possible mechanisms, all focused around genotoxicity, are 

moderately supported as the underlying mechanism for induction of haematological malignancies in humans. Further research is needed 

to decide which of the mechanisms is the most 

important.

5. Evaluation

There is sufficient evidence in humans for the 

carcinogenicity of formaldehyde. Formaldehyde 

causes cancer of the nasopharynx and leukaemia.

Also, a positive association has been observed 

between exposure to formaldehyde and sinonasal 

cancer.

There is sufficient evidence in experimental 

animals for the carcinogenicity of formaldehyde.

The Working Group was not in full agreement on the evaluation of formaldehyde causing 

leukaemias in humans, with a small majority 

viewing the evidence as sufficient of carcinogenicity and the minority viewing the evidence 

as limited. Particularly relevant to the discussions regarding sufficient evidence was a recent 

study accepted for publication which, for the first 

time, reported aneuploidy in blood of exposed 

workers characteristic of myeloid leukaemia and 

myelodysplastic syndromes, with supporting 

information suggesting a decrease in the major 

circulating blood-cell types and in circulating 

haematological precursor cells. The authors and 

Working Group felt that this study needed to be 

replicated.

Formaldehyde is carcinogenic to humans 

(Group 1).

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